Comprehensive Genomic Assessment of Advanced-Stage GI Stromal Tumors Using the Japanese National Center for Cancer Genomics and Advanced Therapeutics Database.

Abstract

Clinical utility of comprehensive genomic profiling (CGP) for precision medicine has become evident. Although there are several reports on the genomic landscape of GI stromal tumors (GISTs), large-scale data specific to GIST are limited, especially in Asia. Additionally, the applicability of molecular-targeted agents identified using CGP has not been extensively examined. We investigated the status of genomic alterations in Japanese patients with advanced GISTs using the National Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database to identify novel treatment strategies and drug development. We retrospectively reviewed the clinical and CGP data of patients with advanced-stage GIST registered in the C-CAT database to assess the genomic landscape and potential actionable alterations. Data from 144 patients were reviewed. Oncogenic alterations were detected frequently in <i>KIT</i> (78%), <i>CDKN2A</i> (37%), <i>CDKN2B</i> (29%), <i>RB1</i> (11%), <i>STK11</i> (10%), <i>TP53</i> (9%), <i>PDGFRA</i> (6%), and <i>SDHB</i> (6%). Loss of <i>CDKN2A</i>/<i>CDKN2B</i> was only observed in <i>KIT/PDGFRA</i>-mutated GISTs, while alterations in <i>SDHA/SDHB</i> were only detected in <i>KIT/PDGFRA</i> wild-type GISTs. Among 119 <i>KIT/PDGFRA</i>-mutated GISTs, 95 (80%) had oncogenic genomic alterations and 29 (24%) had actionable alterations, excluding <i>KIT</i> and <i>PDGFRA</i>. However, among 25 <i>KIT/PDGFRA</i> wild-type GISTs, 22 (88%) had oncogenic alterations and 11 (44%) had actionable alterations. Representative candidate drugs for genome-matched therapies in <i>KIT/PDGFRA</i>-mutated and wild-type GISTs were as follows: pembrolizumab for tumor mutation burden-high in one and two patients, respectively; poly-adenosine diphosphate ribose polymerase inhibitors for alterations related to homologous recombination deficiency in 12 and one patient, respectively; NTRK inhibitor for <i>ETV6-NTRK3</i> fusion in one with <i>KIT/PDGFRA</i> wild-type GIST; and human epidermal growth factor receptor 2-antibody-drug conjugate in one with <i>KIT/PDGFRA</i>-mutated GIST. This study highlights the genomic landscape of advanced GISTs and the important role of CGP in identifying rational molecular-targeted therapeutic options.